RESUMO
OBJECTIVE: Recombinant human soluble thrombomodulin (rhsTM) is a therapeutic agent for sepsis-induced disseminated intravascular coagulation (DIC) and is associated with bleeding events. rhsTM is a renal excretion drug; however, information on the role of rhsTM in renal function is limited. MATERIALS AND METHODS: In this retrospective observational study, we assessed rhsTM-associated bleeding events according to the renal function of patients with sepsis-induced DIC. We analyzed the data of 79 patients administered a standard-dose of rhsTM for sepsis-induced DIC, at a single center. Patients were classified based on estimated glomerular filtration rate (eGFR). We measured fresh bleeding events following rhsTM administration, DIC score efficacy, and 28-day mortality. RESULTS: Fresh bleeding events were observed in 15 patients, with a significant difference in the eGFR, platelet count, and DIC scores. Furthermore, fresh bleeding events tended to increase with the deterioration of renal function (p = 0.039). The DIC scores in all renal function groups decreased after -rhsTM administration. Additionally, the 28-day mortality was less than 30% in all groups. CONCLUSION: Our results indicate that the effectiveness of the standard-dose of rhsTM is not related to renal function. However, standard-dose rhsTM therapy could potentially increase the risk of adverse bleeding events with severe renal function equivalent to G5.
Assuntos
Coagulação Intravascular Disseminada , Sepse , Humanos , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/etiologia , Trombomodulina/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Hemorragia , Sepse/complicações , Sepse/tratamento farmacológico , Rim/fisiologia , Resultado do TratamentoRESUMO
Research suggests that thioether analogs of vitamin K3 (VK3) can act to preserve the phosphorylation of epidermal growth factor receptors by blocking enzymes (phosphatases) responsible for their dephosphorylation. Additionally, these derivatives can induce apoptosis via mitogen-activated protein kinase and caspase-3 activation, inducing reactive oxygen species (ROS) production, and apoptosis. However, vitamin K1 exhibits only weak inhibition of phosphatase activity, while the ability of VK3 to cause oxidative DNA damage has raised concerns about carcinogenicity. Hence, in the current study, we designed, synthesized, and screened a number of VK3 analogs for their ability to enhance phosphorylation activity, without inducing off-target effects, such as DNA damage. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay revealed that each analog produced a different level of cytotoxicity in the Jurkat human leukemia cell line; however, none elicited a cytotoxic effect that differed significantly from that of the control. Of the VK3 analogs, CPD5 exhibited the lowest EC50, and flow cytometry results showed that apoptosis was induced at final concentrations of ≥10 µM; hence, only 0.1, 1, and 10 µM were evaluated in subsequent assays. Furthermore, CPD5 did not cause vitamin K-attributed ROS generation and was found to be associated with a significant increase in caspase 3 expression, indicating that, of the synthesized thioether VK3 analogs, CPD5 was a more potent inducer of apoptosis than VK3. Hence, further elucidation of the apoptosis-inducing effect of CPD5 may reveal its efficacy in other neoplastic cells and its potential as a medication.